scholarly journals Crystal structure of human prion protein bound to a therapeutic antibody

2009 ◽  
Vol 106 (8) ◽  
pp. 2554-2558 ◽  
Author(s):  
S. V. Antonyuk ◽  
C. R. Trevitt ◽  
R. W. Strange ◽  
G. S. Jackson ◽  
D. Sangar ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Prion Protein ◽  
Therapeutic Antibody ◽  
Human Prion Protein

scholarly journals Structural studies on the folded domain of the human prion protein bound to the Fab fragment of the antibody POM1

2012 ◽  
Vol 68 (11) ◽  
pp. 1501-1512 ◽  
Author(s):  
Pravas Kumar Baral ◽  
Barbara Wieland ◽  
Mridula Swayampakula ◽  
Magdalini Polymenidou ◽  
Muhammad Hafiz Rahman ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Prion Protein ◽  
Prion Diseases ◽  
Passive Immunization ◽  
Antibody Fragment ◽  
Binding Mode ◽  
Cellular Prion Protein ◽  
Fab Fragment ◽  
Human Prion Protein

Prion diseases are neurodegenerative diseases characterized by the conversion of the cellular prion protein PrPcinto a pathogenic isoform PrPsc. Passive immunization with antiprion monoclonal antibodies can arrest the progression of prion diseases. Here, the crystal structure of the Fab fragment of an antiprion monoclonal antibody, POM1, in complex with human prion protein (huPrPc) has been determined to 2.4 Å resolution. The prion epitope of POM1 is in close proximity to the epitope recognized by the purportedly therapeutic antibody fragment ICSM18 Fab in complex with huPrPc. POM1 Fab forms a 1:1 complex with huPrPcand the measuredKdof 4.5 × 10−7 Mreveals moderately strong binding between them. Structural comparisons have been made among three prion–antibody complexes: POM1 Fab–huPrPc, ICSM18 Fab–huPrPcand VRQ14 Fab–ovPrPc. The prion epitopes recognized by ICSM18 Fab and VRQ14 Fab are adjacent to a prion glycosylation site, indicating possible steric hindrance and/or an altered binding mode to the glycosylated prion proteinin vivo. However, both of the glycosylation sites on huPrPcare positioned away from the POM1 Fab binding epitope; thus, the binding mode observed in this crystal structure and the binding affinity measured for this antibody are most likely to be the same as those for the native prion proteinin vivo.

scholarly journals Probing the N-Terminal β-Sheet Conversion in the Crystal Structure of the Human Prion Protein Bound to a Nanobody

2014 ◽  
Vol 136 (3) ◽  
pp. 937-944 ◽  
Author(s):  
Romany N. N. Abskharon ◽  
Gabriele Giachin ◽  
Alexandre Wohlkonig ◽  
Sameh H. Soror ◽  
Els Pardon ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Prion Protein ◽  
Human Prion Protein ◽  
Β Sheet

scholarly journals The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein

RSC Advances ◽  
2021 ◽  
Vol 11 (42) ◽  
pp. 25901-25911
Author(s):  
Preeti Rana Sirohi ◽  
Anchala Kumari ◽  
Nikita Admane ◽  
Pallavi Somvanshi ◽  
Abhinav Grover
Keyword(s):  
Prion Protein ◽  
Amyloid Aggregation ◽  
Drug Lead ◽  
Human Prion Protein

Polydatin is found to be a pharmacologically-significant scaffold that can bind to the rPrPres repertoire and inhibit its conversion to the highly infectious and neurotoxic PrPSc-like form, thus acting like a promising anti-prion drug lead.

scholarly journals Sensitive protein misfolding cyclic amplification of sporadic Creutzfeldt–Jakob disease prions is strongly seed and substrate dependent

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maxime Bélondrade ◽  
Simon Nicot ◽  
Charly Mayran ◽  
Lilian Bruyere-Ostells ◽  
Florian Almela ◽  
...  
Keyword(s):  
Prion Protein ◽  
Protein Misfolding ◽  
Protein Misfolding Cyclic Amplification ◽  
Bank Voles ◽  
Substrate Dependence ◽  
Brain Extracts ◽  
Jakob Disease ◽  
Human Prion Protein

AbstractUnlike variant Creutzfeldt–Jakob disease prions, sporadic Creutzfeldt–Jakob disease prions have been shown to be difficult to amplify in vitro by protein misfolding cyclic amplification (PMCA). We assessed PMCA of pathological prion protein (PrPTSE) from 14 human sCJD brain samples in 3 substrates: 2 from transgenic mice expressing human prion protein (PrP) with either methionine (M) or valine (V) at position 129, and 1 from bank voles. Brain extracts representing the 5 major clinicopathological sCJD subtypes (MM1/MV1, MM2, MV2, VV1, and VV2) all triggered seeded PrPTSE amplification during serial PMCA with strong seed- and substrate-dependence. Remarkably, bank vole PrP substrate allowed the propagation of all sCJD subtypes with preservation of the initial molecular PrPTSE type. In contrast, PMCA in human PrP substrates was accompanied by a PrPTSE molecular shift during heterologous (M/V129) PMCA reactions, with increased permissiveness of V129 PrP substrate to in vitro sCJD prion amplification compared to M129 PrP substrate. Combining PMCA amplification sensitivities with PrPTSE electrophoretic profiles obtained in the different substrates confirmed the classification of 4 distinct major sCJD prion strains (M1, M2, V1, and V2). Finally, the level of sensitivity required to detect VV2 sCJD prions in cerebrospinal fluid was achieved.

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